The lymphoid system performs critical functions in animals that include preventing and combating infection, and surveillance and immune elimination of tumor cells. Loss of immune function leads to an immunocompromised status that can predispose the host to serious and life-threatening disease. Functional abnormalities may be present in any of the elements that participate in mediating an immune response, e.g., cellular or humoral elements such as granulocytes, lymphocytes, complement, antibody, or cytokines.
The immune system is a network of cells adapted to protect the organism against pathogens and cells that are not recognized as “self.” Once the immune system is activated, it enlists the participation of a variety of cells and molecules to mount an effector function designed to eliminate the “non-self” entity within the body. Lymphocytes are cells of the immune system that are capable of specifically recognizing and selectively eliminating foreign entities. By contrast to other cells of the immune system, such as neutrophils which are considered non-specific in their reactions to invaders, the characteristics of lymphocytes confer specificity, diversity, memory and self/nonself recognition to the immune response.
There are two major populations of lymphocytes: B lymphocytes and T lymphocytes. B lymphocytes originate and mature within the bone marrow and are responsible for formation of antibody molecules. T lymphocytes also arise from the bone marrow but mature in the thymus. There are two major subpopulations of T-cells: T helper cells and T cytotoxic cells. The two types of T cells can be distinguished by the presence of one of two membrane glycoproteins, either CD4 or CD8. The T-helper cells (which express CD4) when activated by antigen-complexes (foreign molecules coupled to special proteins) respond by secreting various growth factors known collectively as cytokines. These cytokines are signals that activate other cells of the immune system, including the T-cytotoxic cells. The T-cytotoxic cells (which express CD8) when activated, proliferate and differentiate into cytotoxic T lymphocytes (CTL) which are able to monitor for and eliminate from the body pathogenic cells, foreign cells, virus-infected cells, and tumor cells. The normal development, maturation and differentiation of T lymphocytes are regulated by various peptide factors.
The thymus, the primary site of T cell production, is formed during fetal development by seeding of the thymic primordium by blood-borne lymphocyte progenitor cells T from the fetal liver (Akashi et al., Curr. Opin. Immunol. 12: 144, 2000). The development of mature T cells is dependent on interactions between the developing lymphocyte precursors and the thymic stroma, made up of thymic epithelial cells and mesenchyme-derived cells (Anderson et al., Annu. Rev. Immunol. 14: 73, 1996). Thymocyte development has been defined by cell surface expression of developmentally regulated markers: the most immature CD4−CD8− double-negative (DN) thymocytes give rise to CD4+CD8+ double-positive (DP) thymocytes, which give rise to mature CD4+CD8− single-positive (SP) and CD4−CD8+ SP T cells. The DN population can be further subdivided by the expression of CD44 and CD25: CD44+CD25− (DN1) cells differentiate into CD44+CD25+ (DN2) cells, which give rise to CD44−CD25+ (DN3) cells, which finally become the most mature CD44−CD25− (DN4) DN population. The DN4 cells may pass through an intermediate population expressing either coreceptor alone before becoming DP cells. This intermediate population, most commonly expressing CD8, is known as immature single positive (ISP) cells. Progression beyond the DN3 stage is dependent on successful rearrangement of a TCRβ-chain gene and pre-TCR signaling, whereas differentiation from DP to mature SP cell is dependent on the expression and positive selection of an αβTCR (Von Boehmer et al., Immunol. Rev. 191: 62, 2003; Ceredig and Rolink, Nat. Rev. Immunol. 2: 888, 2002).
The most immature DN1 cells express CD45 and CD117, but are not fully committed to the T cell lineage. The DN1 population contains cells that can give rise to T, B, NK, and dendritic cells (Akashi, supra). As thymocytes proceed along their program of differentiation they become progressively more committed to the T cell lineage, and DN3 cells that have TCRβ VDJ arrangements are irreversibly committed (Ceredig and Rolink, supra).